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BACKGROUND: Gait disturbances are a frequent symptom in CACNA1A disorders. Even though, data about their severity and progression are lacking and no CACNA1A-specific scale or assessment for gait is available. METHODS: We applied a gait assessment protocol in 20 ambulatory patients with genetically confirmed CACNA1A disorders and 39 matched healthy controls. An instrumented gait analysis (IGA) was performed by means of wearable sensors in basal condition and after a treadmill/cycloergometer challenge in selected cases. RESULTS: CACNA1A patients displayed lower gait speed, shorter steps with increased step length variability, a reduced landing acceleration as well as a reduced range of ankle motion compared to controls. Furthermore, gait-width in patients with episodic CACNA1A disorders was narrower as compared to controls. In one patient experiencing mild episodic symptoms after the treadmill challenge, the IGA was able to detect a deterioration over all gait parameters. CONCLUSIONS: In CACNA1A patients, the IGA with wearable sensors unravels specific gait signatures which are not detectable at naked eye. These features (narrow-based gait, lower landing acceleration) distinguish these patients from other ataxic disorders and may be target of focused rehabilitative interventions. IGA can potentially be applied to monitor the neurological fluctuations associated with CACNA1A disorders.
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Ataxia , Canales de Calcio , Análisis de la Marcha , Ataxia/diagnóstico , Ataxia/genética , Canales de Calcio/genética , Marcha , Humanos , CaminataRESUMEN
OBJECTIVES: CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). EEG is applied to study their episodic manifestations, but findings in the intervals did not gain attention up to date. METHODS: We analyzed repeated EEG recordings performed between 1994 and 2019 in a large cohort of genetically confirmed CACNA1A patients. EEG findings were compared with those of CACNA1A-negative phenocopies. A review of the related literature was performed. RESULTS: 85 EEG recordings from 38 patients (19 EA2, 14 FHM1, 5 SCA6) were analyzed. Baseline EEG was abnormal in 55% of cases (12 EA2, 9 FHM1). The most common finding was a lateralized intermittent slowing, mainly affecting the temporal region. Slowing was more pronounced after a recent attack but was consistently detected in the majority of patients also during the follow-up. Interictal epileptic discharges (IEDs) were detected in eight patients (7 EA2,1 FHM1). EEG abnormalities and especially IEDs were significantly associated with younger age at examination (16 ± 9 vs 43 ± 21 years in those without epileptic changes, p = 0.003) and with earlier onset of disease (1 (1-2) vs 12 (5-45) years, p = 0.0009). EEG findings in CACNA1A-negative phenocopies (n = 15) were largely unremarkable (p = 0.03 in the comparison with CACNA1A patients). CONCLUSIONS: EEG abnormalities between attacks are highly prevalent in episodic CACNA1A disorders and especially associated with younger age at examination and earlier disease onset. Our findings underpin an age-dependent effect of CACNA1A variants, with a more severe impairment when P/Q channel dysfunction manifests early in life.
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Epilepsia , Migraña con Aura , Ataxias Espinocerebelosas , Canales de Calcio/genética , Humanos , FenotipoRESUMEN
BACKGROUND: To investigate the genetic and environmental factors responsible for phenotype variability in a family carrying a novel CACNA1A missense mutation. Mutations in the CACNA1A gene were identified as responsible for at least three autosomal dominant disorders: FHM1 (Familial Hemiplegic Migraine), EA2 (Episodic Ataxia type 2), and SCA6 (Spinocerebellar Ataxia type 6). Overlapping clinical features within individuals of some families sharing the same CACNA1A mutation are not infrequent. Conversely, reports with distinct phenotypes within the same family associated with a common CACNA1A mutation are very rare. CASE PRESENTATION: A clinical, molecular, neuroradiological, neuropsychological, and neurophysiological study was carried out in proband and his carrier mother. The new heterozygous missense variant c.4262G > A (p.Arg1421Gln) in the CACNA1A gene was detected in the two affected family members. The proband showed a complex clinical presentation characterized by developmental delay, poor motor coordination, hemiplegic migraine attacks, behavioral dysregulation, and EEG abnormalities. The mother showed typical episodic ataxia attacks during infancy with no other comorbidities and mild cerebellar signs at present neurological evaluation. CONCLUSIONS: The proband and his mother exhibit two distinct clinical phenotypes. It can be hypothesized that other unknown modifying genes and/or environmental factors may cooperate to generate the wide intrafamilial variability.
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Ataxia/genética , Canales de Calcio/genética , Migraña con Aura/genética , Nistagmo Patológico/genética , Niño , Familia , Humanos , Masculino , Mutación Missense , FenotipoRESUMEN
The P/Q-type CaV2.1 channel regulates neurotransmitter release at neuromuscular junctions (NMJ) and many central synapses. CACNA1A encodes the pore-containing α1A subunit of CaV2.1 channels. In humans, de novo CACNA1A mutations result in a wide spectrum of neurological, neuromuscular, and movement disorders, such as familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), as well as a more recently discovered class of more severe disorders, which are characterized by ataxia, hypotonia, cerebellar atrophy, and cognitive/developmental delay. Heterologous expression of CaV2.1 channels has allowed for an understanding of the consequences of CACNA1A missense mutations on channel function. In contrast, a mechanistic understanding of how specific CACNA1A mutations lead in vivo to the resultant phenotypes is lacking. In this review, we present the zebrafish as a model to both study in vivo mechanisms of CACNA1A mutations that result in synaptic and behavioral defects and to screen for effective drug therapies to combat these and other CaV2.1 channelopathies.
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BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.
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Canales de Calcio/genética , Trastornos Mentales/genética , Enfermedades del Sistema Nervioso/genética , Adolescente , Adulto , Ataxia/genética , Ataxia Cerebelosa/genética , Niño , Preescolar , Comorbilidad , Escolaridad , Femenino , Genotipo , Humanos , Masculino , Trastornos Mentales/psicología , Trastornos Migrañosos/genética , Enfermedades del Sistema Nervioso/psicología , Pruebas Neuropsicológicas , Fenotipo , Desempeño Psicomotor , Estudios Retrospectivos , Ataxias Espinocerebelosas/genética , Adulto JovenRESUMEN
Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wild-type (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the CaV2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of CaV2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.
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Analgésicos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/genética , Ataxia Cerebelosa/tratamiento farmacológico , Depresión de Propagación Cortical/efectos de los fármacos , Trastornos Migrañosos/tratamiento farmacológico , Migraña con Aura/tratamiento farmacológico , Pregabalina/farmacología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Canales de Calcio Tipo N/metabolismo , Ataxia Cerebelosa/diagnóstico por imagen , Ataxia Cerebelosa/metabolismo , Ataxia Cerebelosa/patología , Imagen de Difusión por Resonancia Magnética , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/patología , Migraña con Aura/diagnóstico por imagen , Migraña con Aura/metabolismo , Migraña con Aura/patología , Mutación , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Transmisión SinápticaRESUMEN
Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α1A subunit of voltage-gated CaV2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation ('FHM1 R192Q mice') exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine.
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Depresión de Propagación Cortical/genética , Inflamación/complicaciones , Inflamación/patología , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/fisiopatología , Animales , Sitios de Unión , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Análisis por Conglomerados , Modelos Animales de Enfermedad , Epistasis Genética , Ontología de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Trastornos Migrañosos/genética , Mapas de Interacción de Proteínas/genética , Factores de Transcripción/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: On trigeminal ganglion neurons, pain-sensing P2X3 receptors are constitutively inhibited by brain natriuretic peptide via its natriuretic peptide receptor-A. This inhibition is associated with increased P2X3 serine phosphorylation and receptor redistribution to non-lipid raft membrane compartments. The natriuretic peptide receptor-A antagonist anantin reverses these effects. We studied whether P2X3 inhibition is dysfunctional in a genetic familial hemiplegic migraine type-1 model produced by introduction of the human pathogenic R192Q missense mutation into the mouse CACNA1A gene (knock-in phenotype). This model faithfully replicates several properties of familial hemiplegic migraine type-1, with gain-of-function of CaV2.1 Ca(2+) channels, raised levels of the algogenic peptide calcitonin gene-related peptide, and enhanced activity of P2X3 receptors in trigeminal ganglia. RESULTS: In knock-in neurons, anantin did not affect P2X3 receptor activity, membrane distribution, or serine phosphorylation level, implying ineffective inhibition by the constitutive brain natriuretic peptide/natriuretic peptide receptor-A pathway. However, expression and functional properties of this pathway remained intact together with its ability to downregulate TRPV1 channels. Reversing the familial hemiplegic migraine type-1 phenotype with the CaV2.1-specific antagonist, ω-agatoxin IVA restored P2X3 activity to wild-type level and enabled the potentiating effects of anantin again. After blocking calcitonin gene-related peptide receptors, P2X3 receptors exhibited wild-type properties and were again potentiated by anantin. CONCLUSIONS: P2X3 receptors on mouse trigeminal ganglion neurons are subjected to contrasting modulation by inhibitory brain natriuretic peptide and facilitatory calcitonin gene-related peptide that both operate via complex intracellular signaling. In the familial hemiplegic migraine type-1 migraine model, the action of calcitonin gene-related peptide appears to prevail over brain natriuretic peptide, thus suggesting that peripheral inhibition of P2X3 receptors becomes insufficient and contributes to trigeminal pain sensitization.
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Migraña con Aura/genética , Migraña con Aura/metabolismo , Péptido Natriurético Encefálico/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Células Receptoras Sensoriales/patología , Ganglio del Trigémino/patología , Animales , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Ratones , Migraña con Aura/patología , Modelos Biológicos , Péptidos Cíclicos/farmacología , Fenotipo , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores del Factor Natriurético Atrial/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Canales Catiónicos TRPV/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/metabolismo , omega-Agatoxina IVA/farmacologíaRESUMEN
Migraine is a neurovascular brain disorder suggested to be due to dysfunction of the trigeminovascular system with sensitization of trigeminal ganglion (TG) nociceptors. Since the neuropeptide calcitonin gene-related peptide (CGRP) has been established as a key player in the pathogenesis of migraine, CGRP receptor antagonists have been considered useful compounds to block headache originating from hyperactivation of such TG neurons. Whereas there is some information on the expression of CGRP receptors in postmortem human tissue, data are lacking for migraineurs suffering from common or genetic migraine. To help to clarify these issues it is very useful to study a transgenic knock-in (KI) mouse model of hemiplegic migraine expressing a R192Q missense mutation in the α1 subunit of CaV2.1 calcium channels previously found in patients with familial hemiplegic migraine type-1 (FHM-1). The aim of the present study, therefore, was to compare CGRP receptor expression and function in wildtype (WT) versus KI mouse TG. The principal components of the CGRP receptor, namely the CLR and RAMP-1 proteins, were similarly expressed in WT and KI TG neurons (in situ or in culture) and responded to exogenous CGRP with a strong rise in cAMP concentration. Hence, the previously reported phenotype of sensitization of KI TG neurons is not due to up-regulation of CGRP receptors but is likely caused by a constitutively larger release of CGRP. This observation implies that, in FHM-1 TG, normal TG sensory neuron signaling can be restored once the extracellular concentration of CGRP returns to control level with targeted treatment.
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Canales de Calcio Tipo N/genética , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Ganglio del Trigémino/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Proteína Similar al Receptor de Calcitonina/metabolismo , Células Cultivadas , Ataxia Cerebelosa/genética , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trastornos Migrañosos/genética , Mutación Missense , Neuronas/metabolismo , Cultivo Primario de Células , Proteína 1 Modificadora de la Actividad de Receptores/metabolismoRESUMEN
Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered.